PROJECT SUMMARY Low back pain is a global health epidemic commonly associated with painful intervertebral disc (IVD) degeneration (IDD) and its increasing incidence involves economic costs over $100 billion. Research into mechanisms and novel treatments for IDD is a major research priority. Important recent studies provide evidence that type 2 diabetes mellitus (T2DM) and diet can increase painful IDD and spine surgery complications. Establishing a mechanistic relationship between T2DM and IDD may result in novel therapies for T2DM patients and all IDD patients. Our broad goal is to characterize and improve understanding of mechanisms for T2DM- and diet-induced IDD and to develop safe and effective treatments to maintain a healthy spine and to slow the progression of painful IDD. Little research investigates relationships between diet, T2DM, and IDD and our preliminary data provide among the first causal relationships. Our data suggest that DM-induced IDD involves ectopic calcifications and that reducing the accumulation of advanced glycation endproducts (AGEs) and pro-inflammatory cytokines may help mitigate some of the observed IDD. The proposed studies test our overall hypothesis that dietary ingestion of AGEs and T2DM induces pathological and age-accelerated IDD due to AGE accumulation systemically and also in spinal tissues leading to increased pro-inflammatory cytokines, crosslinking, and ectopic calcifications of IVDs and endplates (EPs). We believe these ectopic calcifications and AGE associated crosslinks create stress concentrations and brittle material behaviors that are partially responsible for the microfractures, fissures, and fibrotic healing attempts commonly observed in painful human IDD in both DM and non-DM patients. Aim 1 will test this hypothetical model using T2DM, high-AGE ingestion, and Receptor for AGE (RAGE) knockout mice to investigate the roles of AGEs and pro-inflammatory cytokines in contributing to IDD and ectopic calcifications. Aim 2 investigates AGE and hyperglycemia effects on IVD organs in order to distinguish between systemic and spine tissue level effects while identifying pathways for IDD and ectopic calcification. Aim 3 will test for direct relationships between AGEs, IDD and ectopic calcifications in human IVDs and cells from autopsy. This project is significant because of the tremendous health burden of IDD, the new insights that will be gained regarding causes and treatment of IDD, and the complementary mouse and human studies. The approach is innovative because there are remarkably few studies relating T2DM and IDD, and our novel hypothetical model provides a framework that may impact IDD treatments for both T2DM and non-T2DM patients. Successful completion of this project will provide new insights into the relationships between systemic health and IDD in mice and humans with investigations that may result in novel treatments relevant to all IDD patients.